The oncogenic gamma-herpesvirus Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS), a tumor of endothelial origin, and two B cell disorders, primary effusion lymphoma and multicentric Castleman's disease. KS is the most common AIDS-associated malignancy and one of the most prevalent cancers overall amongst populations co-infected with HIV and KSHV. Although HAART has greatly reduced KS incidence in developed countries, KS remains a cause of considerable morbidity and mortality worldwide, and effective and inexpensive novel therapies are badly needed. The primary goal of this project is to determine whether heme oxygenase-1 (HO-1), a cellular enzyme that is strongly induced in KSHV-infected endothelial cells (EC) and highly expressed in KS biopsy tissue, is a viable therapeutic target for KS. HO-1 metabolizes heme, a potentially toxic pro-oxidant molecule, to by-products (carbon monoxide, bilirubin, iron) with cytoprotective, proliferative and anti-apoptotic properties. KS spindle cells engulf and degrade heme- containing erythrocytes that extravasate into the tumor, and this distinctive capacity predicts tha KS tumor cells are particularly reliant on HO-1 expression and activity to facilitate degradation o excess heme substrate. We hypothesize that KSHV-induction of HO-1 allows spindle cells to thrive in a high-heme environment, and that pharmacological manipulation of HO-1 should be evaluated for KS therapy. Our preliminary data that support this hypothesis show that HO-1 is required for efficient KSHV infection of EC, that KSHV-infected EC use exogenous heme as a growth stimulus in a HO-1-dependent manner, and that KSHV encodes specific factors that regulate HO-1 expression during different phases of virus infection. Importantly, inhibition of HO-1 activity with stannic mesoporphyrin (SnMP), a HO-1 inhibitor approved for the treatment of neonatal jaundice, attenuated both the pro-viral and pro-growth activity of HO-1. Based on these findings, we propose three complementary yet independent Aims to define the mechanism(s) through which: (i) KSHV induces endothelial HO-1, (ii) HO-1 facilitates KSHV infection of EC, and (iii) KSHV-induced HO-1 promotes tumorigenesis. These Aims integrate genetic and mechanistic EC-based in vitro infection models, and in vivo anti-viral and anti- tumor studies using a recently-established humanized mouse model (Hu-BLT model) for KSHV infection and a tumor-implant model for tumorigenesis. Data will be used to inform the design of a Phase I/II clinical trial run by the AIDS Malignancy Consortium designed to test pharmaceutical grade SnMP in AIDS/KS patients. Overall, this innovative translational study is expected to exert an impact on the KSHV/KS field by identifying and characterizing a novel virus-host interaction, and establishing whether HO-1 is a viable therapeutic target for KS. Knowledge gained should impact the broader fields of anti-tumor therapy and tumor virus pathogenesis.